Colorectal cancer has many diet and lifestyle factors that contribute to the etiology. Data suggest that differences in etiology exist by tumor site, age, and sex, and that certain exposures modify the effects of others, indicating the importance of various diet and lifestyle factors in certain environments. Major factors that modify the effects of other risk factors are'use of aspirin and ibuprofen-type drugs. Our previous data have shown that NSAIDs interact with a variety of diet and lifestyle factors, including dietary fat, BMI, insulin- related genes, and estrogen. We hypothesize that genetic variation in an inflammation-related signaling pathway and in a pathway where inflammation, insulin and estrogen converge (designated as a metabolic signaling pathway) will most likely have implications for disease risk. We propose to study two pathways which have not previously been studied with colorectal cancer. We utilize data previously collected on 2780 incident cases of colorectal cancer and 3025 population-based controls to obtain a better understanding of the inter-relationship between inflammation, insulin, and estrogen. We examine known functional polymorphisms and evaluate haplotypes in candidate genes in an inflammation-related pathway (IL6, IL8, IL10, NFKB, TNF-A, IL4, IL1, ILIRA and IFNG) and genes located at key junctions where other cellular signaling pathways converge which we describe as a metabolic signaling pathway (SOC1, SOC2, AKT, FRAP1 (mTOR), TSC1, TSC2, P13K, LKB, AMP, PTEN, S6K.VEGF, STAT1, STAT6, JNK1, and pSSMAPK). We will test associations between genetic polymorphisms and haplotypes of these genes with colorectal cancer. We will evaluate the interaction of these genes with NSAIDs/aspirin, estrogen, BMI, dietary fat, antioxidants, and physical activity. We will evaluate associations of these polymorphisms/haplotypes with specific types of tumor mutations. We will utilize statistical methods to gain insight into how these genes relate to specific disease pathways and how genes inter-relate along these pathways. We include test of functionality for all genes and SNPs identified as being assocatied with CRC and we will validate study findings using statistical techniques that allow for test and validation. Identification of polymorphisms or haplotypes that are relevant to colorectal cancer will advance our understanding of etiology, may lead to specific health recommendations, and can identify targets for drug therapy.